LONG-TERM EFFECTS: COMPARING KETAMINE INFUSIONS WITH KETAMINE COMBINATION THERAPY

Long-Term Effects of Ketamine Infusions in Comparison to Combination

Therapy involving additional rTMS, Neurofeedback and Psychotherapy - A
Retrospective Survey Study of Subjective Effects

Johanna Kreßner, B.Sc., Anja Frank, M.A., Mario Scheib, M.D.

Authors Note
All authors work for “Privatpraxis Dr. Scheib Berlin”, a clinic where patients are treated with
neuromodulation techniques, ketamine infusions and psychotherapy.
Correspondence concerning this article should be addressed to Dr. Mario Scheib,
Privatpraxis Dr. Scheib, Lützenstr. 3-4, 10711 Berlin. Email: dr.scheib@psychosomatik.com

Abstract
Background: The anesthetic Ketamine has been shown to exert rapid effects in a variety of mood
disorders, especially in depression. Recent studies have demonstrated that Ketamine can improve
neuroplasticity, the brain’s ability to adapt and form new neuronal connections (Aleksandrova &
Phillips, 2021). Aim: To examine the long-term effects of Ketamine without and in combination with
other techniques for induced modulation. Method: 26 patients, some of them who only received
ketamine and some of them who received additionally repetitive transcranial stimulation (rTMS),
Neurofeedback (NF) and Psychotherapy, were asked to estimate (partially retrospectively) how their
mood was expressed pre-treatment, post-treatment and at the time of the survey. The results were
analyzed by using descriptive statistics. Results: 25 patients showed a long-term improved effect in
their mood after the treatment, even though the treatment was carried out a long time ago. Patients
who received a combination of treatments showed better mood improvements than patients who
solely were administered ketamine infusions. Conclusions: Patients who received ketamine therapy
exhibited promising lasting effects. Their mood changed considerably, regardless of whether they
only got ketamine infusions or a combination treatment, but combining ketamine with other
treatments seems to have a superior effect.

Keywords: Ketamine, Psychotherapy, Substance Assisted Therapy, Psychedelics,

Retrospective Study, rTMS, Neurofeedback

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LONG-TERM EFFECTS: COMPARING KETAMINE INFUSIONS WITH KETAMINE COMBINATION THERAPY

Introduction
Ketamine, an NMDA receptor antagonist, is known to have immediate antidepressant effects,
unlike other traditional antidepressant medications that take weeks to produce noticeable
effects. The primary mechanism of action of ketamine is believed to be the promotion of
"brain plasticity synaptic, structural, and functional changes" in the prefrontal cortex's
pyramidal neurons, allowing the brain to form new functional networks (Aleksandrova &
Phillips, 2021, p.1). Recent studies have also suggested that ketamine may stimulate
hippocampal neurogenesis. These underlying mechanisms could explain why ketamine is
effective in treating depression, especially treatment-resistant depression (TRD).Typically,
ketamine infusions or ketamine-assisted psychotherapy (KAP) are only considered after
pharmacotherapy or psychotherapy has failed to produce satisfactory results (Bahij et al.,
2021). The effects of ketamine on mood can be noticed after the first infusion, but the
immediate effects can last for varying lengths of time, with people suffering from TRD
reportedly benefiting the most (Alnefeesi et al., 2022).

While the short-term positive effects of ketamine have already been demonstrated by several
studies, there are few results on the long-term effects to date. The aim of the study was to
gather results on the long-term effects of KAP and to determine if combination treatment has
an superior effect to just (Duman, Li, Liu, Duric & Aghajanian, 2012; Hasler, 2020; Hirota &
Lambert, 1996; Schoretsanitis & Hasler, 2015; Wei, Chang & Hashimoto, 2020). Repetitive
Transcranial Magnetic Stimulation (rTMS), Neurofeedback and Psychotherapy was
employed. RTMS is conducted by applying externally produced alternating magnetic fields
which act on the brain's nerve cells by stimulating electrical activity and activating (or
inhibiting) them, as well as brain networks (Lefaucheur et al., 2017). Additionally, recent
studies suggest another mode of action for rTMS, that being its glial activation which leads to
anti-inflammatory effects (Luan et al., 2020). Regulatory agencies currently recognize
repetitive transcranial magnetic stimulation as a viable treatment option for patients suffering
from drug-resistant depression (Level A Evidence) and obsessive-compulsive disorder, as
well as a potential therapy for fibromyalgia/neuropathic pain, drug addiction, chronic fatigue
syndrome (CFS) as a Post-Covid-19 symptom (Rolle et al., 2022), gambling disorder and to
treat the consequences of a stroke (Aceves-Serrano et al., 2022; Lefaucheur et al., 2020; Neva
et al., 2020).

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LONG-TERM EFFECTS: COMPARING KETAMINE INFUSIONS WITH KETAMINE COMBINATION THERAPY

Neurofeedback (NF) is also sometimes referred to as "EEG-Biofeedback", although it can be

applied to a number of other imaging modalities, such as fMRI, PET, and Functional Near-
Infrared Spectroscopy (fNIRS). This technique is coupled with a computer screen, allowing
the user to see their brain activity represented as either a graphic replica or a game.
Additionally, operant conditioning is often used in NF, with rewards given for achieving the
desired brainwave e.g., a reward picture flashes up to the performing person (Schneider,
2020). One mechanism of action is the "autonomic regulation of subcognitive systems",
which represents the implicit nature of learning neurofeedback (Gaume et al., 2016, p.894).
Neurofeedback is used for both therapeutic and performance-enhancing purposes, and most
of the research has focused on attention deficit hyperactivity disorder so far (Haus et al.,
2020). Furthermore it is applied as a method to conduct experiments in neuroscience
(Enriquez-Geppert et al., 2017). Ultimately, neurofeedback seeks to help patients learn to
control their behavior and attention, as well as their impulsivity, and to self-regulate their
brain states.

Method
This retrospective cohort study was conducted at Clinic Dr. Scheib in Mallorca (Spain),
where a majority of patients seeking treatment receive a diagnosis of depression
(approximately 80%), with a proportion of these patients exhibiting comorbidities such as
addiction and anxiety disorders, among others. N: 116 patients who received treatment
between April 2017 and February 2021 were invited to participate in the study. The data for
this study were obtained from the medical clinic's software and via SurveyMonkey. All
patients who completed a full treatment and filled out the study completely were included.
Patients who did not fully participate or had insufficient patient information were excluded.
The patients were treated with Ketamine-assisted psychotherapy and in combination some of
them received repetitive transcranial magnetic stimulation (rTMS), hypnosis or
neurofeedback (NF). The patients received an average of 5 ketamine infusions (0.5 mg/kg).
Most of the patients stayed 23 weeks as inpatients or outpatients, and up to 10 weeks as
ambulant patients, with an average of 6 weeks. Some patients received solely ketamine
infusions (n = 5; 19.23%), but the majority (n = 21; 80.77%) received psychotherapy (n = 17;
65.38%), neurofeedback (n = 6; 23.06%) and TMS) (n = 9; 34,62%) in addition to ketamine
infusions.

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LONG-TERM EFFECTS: COMPARING KETAMINE INFUSIONS WITH KETAMINE COMBINATION THERAPY

The study was conducted using SurveyMonkey and was completed by patients over a period
of four weeks. Patient names were abbreviated, enabling the results to be compared with their
corresponding medical records. The survey questionnaire comprised items such as "On a
scale from 1-10, how do you feel?", utilizing a 10-point Likert scale with anchor points
ranging from 0 (very poor) to 10 (excellent), and collected data at three time points: "Before",
"After", and "Present"."

Results

Twenty-six patients aged 19 to 82 years participated in the study, with an average of 2.5 years
since treatment (ranging from 3 to 49 months). 25 out of 26 patients reported sustained
improvements in their mood after the treatment (see Figure 1). The mood before the
treatment measured on a scale from 0 (very bad) to 10 (very good) had a median of Mdn = 2
and M = 1.7, which indicates a bad mood . The mood immediately after the treatment and the
present state was rated on average "6". Therefore, the average number has tripled, and the
mood has gone from a "very bad" to a "good" rating.

Figure 1

Comparison of Long-term Effects in Ketamine vs. Combination Therapy

Note. Assessment of mood before, after treatment and mood at the time of the study.

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LONG-TERM EFFECTS: COMPARING KETAMINE INFUSIONS WITH KETAMINE COMBINATION THERAPY

Of particular note is that the treatments were administered a significant amount of time ago
(see Figure 2), with patients receiving treatment an average of 2 years and 4 months ago.
Patients who received only ketamine treatment received it even further back, with an average
of 2 years and 7 months ago.

Figure 2

Time Passed Since End of Treatment

Note. Average duration since the end of treatments in months.

Discussion and Conclusion

The combination therapy was administered on average 1 year and 11 months ago. Both
patient groups reported improvements in mood even after 2 years, indicating a long-term
positive effect of ketamine infusions. No conclusive results were found in terms of
differentiating between patients who benefited more or less from ketamine infusions.
However, it can be concluded that the combination of ketamine, rTMS, and psychotherapy

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LONG-TERM EFFECTS: COMPARING KETAMINE INFUSIONS WITH KETAMINE COMBINATION THERAPY

demonstrated a particularly positive effect. Based on the results, the treatments significantly
contribute to the improvement of patients' mental state.

Similar results were obtained in the study by Best et al. (2019), in which 28 patients with
treatment-resistant depression were treated with ketamine and rTMS. The Clinical Global
Impression (CGI) rating scales, which measure symptom severity, treatment response, and
treatment efficacy, were used to capture scores before, immediately after, and two years after
treatment. CGI scores were significantly reduced at two years compared to baseline (Best,
Pavel & Haustrup, 2019). Pradhan and Rossi (2020) add that it takes repeated treatments to
achieve significantly improved scores. In particular, rTMS should be applied multiple times
to ensure that the changes in brain activity last longer (Pradhan & Rossi, 2020).

Another factor contributing to the long-term positive effect of ketamine appears to be the
increased willingness to change instigated by the treatment. Prior to treatment, many patients
experienced severe depression, making it difficult to manage their lifestyles independently.
The immediate mood improvement resulting from ketamine infusions led to increased self-
efficacy among many patients. During the initial phase of the survey, conducted via
telephone contact, patients reported improvements in their relationships, financial situations,
and work statuses, leading to an overall enhancement of their lifestyles as existing conflicts
were resolved and acute stress decreased.Additionally other studies about the long-term
effects of ketamine have shown a high drop-out rate (Mathers et al., 2018). The high drop-out
rate can possibly also be explained by the fact that the mood improved after only a few
treatments and therefore no further treatments were undertaken.

The study demonstrated the positive and lasting effects of ketamine infusions explicitly. On
average, patients experienced significant mood changes, and the positive effects were not
limited to the immediate post-treatment period but were also sustained up to two and a half
years later. The data indicate that combining ketamine infusions with rTMS and
psychotherapy leads to the best outcomes. Several patients valued ketamine infusions,
particularly during acute crises.

The findings of the present study suggest a surprising sustainability and even improvement in
patients who had only received ketamine infusions, which is not consistent with previous
research (Wilkinson et al., 2017). This outcome may be attributed to the higher motivation
level of the patients, as well as the pre-selection process that takes place when patients travel

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LONG-TERM EFFECTS: COMPARING KETAMINE INFUSIONS WITH KETAMINE COMBINATION THERAPY

to Mallorca. The pharmacologically-induced period of improvement may have played a

significant role in facilitating important, life-changing decisions that produced a sustained
antidepressant effect.

Further systematic studies are warranted to investigate the impact of life events following
ketamine infusions, as well as possible synergistic effects of rTMS, neurofeedback, and
psychotherapy.

Limitations

The study has some limitations due to the characteristics of the clinic where it was conducted,
resulting in a small sample size with a relatively low response rate and a non-standardized
procedure with different variables. Although most patients seeking treatment showed
depressive symptomatology, some patients came for other diagnoses, which could potentially
bias the results if only patients who experienced positive results participated in the survey.
Additionally, the study primarily includes patients with a high socioeconomic status, as they
had to pay for the treatments themselves. It is important to note that the study was conducted
during the COVID-19 related lockdown, where the overall population experienced increased
depressive and anxiety symptoms, as well as higher overall stress rates. Furthermore,
adolescents and younger people were found to be more affected. Further research is needed to
investigate the influence of life events after ketamine infusions and the potential synergistic
effects of rTMS, neurofeedback, and psychotherapy (Berger, Riedel-Heller, Pabst, Rietschel
& Richter, 2021; Riedel-Heller & Richter, 2021).

The present study does not claim to be representative. Instead, it should be considered a
clinical case series that provides insight into the long-term effects of ketamine, particularly
when combined with other treatments. These findings could serve as a basis for further
research on a larger scale.

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LONG-TERM EFFECTS: COMPARING KETAMINE INFUSIONS WITH KETAMINE COMBINATION THERAPY

Abbreviations

CFS Chronic Fatigue Syndrome

CGI Clinical Global Impression

KAP Ketamine-assisted Psychotherapy

NF Neurofeedback

NMDAR N-Methyl-D-Aspartate Receptor

rTMS Repetitive Magnetic Stimulation

Authors

Johanna Kreßner, B.Sc., Student Clinical Psychologist

Anja Frank, M.A., Clinical Psychologist

Dr. med. Mario Scheib (M.D.), Specialist in Psychosomatic Medicine and Psychotherapy

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